Ibogaine is a drug found in the roots of Tabernanthe iboga, a shrub from Gabon, in equatorial west central Africa. Ibogaine has been known since the 1800's as an agent which at low doses has psychostimulant properties, and at high doses can induce a hallucinatory (oneirophrenic) state. For this reason it has been used in the Gabonese society for initiation ceremonial rites.
Ibogaine has also been used as an adjunctive agent in psychotherapy and psychoanalysis, and more recently has been described as an agent that may be able to suppress symptoms of dependence or withdrawal from addictive drugs. Discovery of this property of ibogaine led to the issuance of a number of U.S. patents to Howard S. Lotsof, including U.S. Pat. No. 4,499,096 (issued in 1985, concerning heroin addiction), U.S. Pat. No. 4,587,243 (issued in 1986, concerning cocaine and amphetamine abuse), U.S. Pat. No. 4,857,523 (issued in 1989, concerning alcohol abuse), U.S. Pat. No. 5,026,697 (issued in 1991, concerning tobacco and nicotine), and U.S. Pat. No. 5,152,994 (issued in 1992, concerning people suffering from multiple drug dependencies).
Lotsof's assertions regarding the usefulness of ibogaine in reducing various types of drug dependencies are consistent with evidence generated in several studies on laboratory animals. For example, in rats, ibogaine reduces morphine self-administration and ameliorates symptoms associated with morphine withdrawal and decreases preference for cocaine consumption; see, e.g., Glick et al 1991, Glick et al 1992, Sershen et al 1992, Cappendijk and Dzoljic 1993, and Sershen et al 1994 (full citations to articles are provided below).
Additional information on various cellular mechanisms involved in ibogaine's activity are provided in Deecher et al 1992, Sershen et al 1992, Glick et al 1993, and Popik et al 1994. For example, it appears that ibogaine inhibits binding to a dopamine transporter site (Sershen et al 1992), to a kappa opioid receptor site (Deecher et al 1992), to a voltage-dependent sodium channel site (Deecher et al 1992), and to an NMDA glutamate receptor ion channel site (Popik et al 1994). It is not clear what functional significance these findings may have, because the studies were conducted using receptor binding assays, and a serious limitation of such assays is that they shed no light on whether an agent acts as an agonist or antagonist, or, indeed, whether its binding activity might produce a mixture of agonist and antagonist effects which cancel out to yield no net effect on receptor function.
The recent report by Popik et al (1994) that ibogaine inhibits binding to an NMDA receptor ion channel site is of special interest in relation to the potential of ibogaine for counteracting drug dependencies. Although the evidence from the Popik et al receptor binding study does not clarify what type of action it may have at the NMDA subtype of glutamate receptor, it has been reported recently that agents which are known antagonists of NMDA receptors can prevent the development of tolerance to opiate analgesics (see Marek et al 1991; Trujillo and Akil 1991; Ben-Eliyahu et al 1992; Tal and Bennett 1993), to benzodiazepine anxiolytics such as diazepam (sold under the trade name VALIUM; Turski et al, PCT patent application WO 94/01094), to cocaine (Pudiak and Bozarth 1993), and to alcohol (Wu et al 1993). Accordingly, it was postulated in Popik et al 1994 that the action of ibogaine in blocking drug tolerance, craving, and dependence may signify that it acts as an antagonist at NMDA receptors.
The Applicant has conducted recent experiments using functional bioassay techniques demonstrating unequivocally that ibogaine does act as an antagonist at NMDA receptors, and that it also acts as an antagonist at sigma receptors. Both of these discoveries are important aspects of this invention, and have not been previously reported.
In addition, the present invention pertains, not to blocking drug addiction mechanisms, but to an entirely separate and distinct use for ibogaine, which involves the reduction or prevention of brain damage caused by ischemia (inadequate blood flow to the brain, as occurs during stroke, cardiac arrest, and trauma), hypoxia (inadequate oxygen supply to the brain, as occurs during suffocation, drowning, carbon monoxide poisoning, etc.), and certain other types of crises or conditions. These crises or conditions generate a process in the central nervous system (CNS) known as "excitotoxicity". Since this subject is complex, additional information is provided below on excitotoxicity, on the role of glutamate as an essential neurotransmitter under healthy conditions and as a deadly neurotoxin under certain abnormal conditions, and on the roles of NMDA receptors and NMDA antagonist drugs under such conditions. This is a brief overview; additional information on these topics is provided in numerous articles and books, including Choi 1988 and Olney 1989 (review articles) and in the multi-volume treatise on the central nervous system edited by Adelman (either the 1987 or the 1995 edition).
Additional newly-developed information on the neuronal circuitry described herein is provided in a co-pending U.S. patent application, Ser. No. 08/381,334, co-invented by the same Applicant herein, entitled "USE OF ALPHA-2 ADRENERGIC DRUGS TO PREVENT ADVERSE EFFECTS OF NMDA RECEPTOR HYPOFUNCTION". The contents of that application are incorporated herein by reference; if that co-pending application has not yet issued as a patent, then it will be opened for public inspection and copying upon issuance of a patent based upon this instant application.